Melanoma is a potentially fatal form of skin cancer that, under the influence of ultraviolet (UV) radiation, arises from isolated melanocytes or melanocytic neoplasms (moles or nevi). Despite efforts to develop new therapeutic modalities, survival rates for patients with advanced melanoma have not improved in recent decades. Preventive measures, such as screening and early detection, can reduce incidence and improve survival in patients with prior history of melanoma or numerous/atypical nevi who are at increased risk for developing melanoma. In addition, a variety of chemopreventive agents including antioxidants and natural products have been considered, but none have conclusively shown benefit in high-risk patients. Conventional cancer chemoprevention usually involves chronic administration of a drug, not taken in conjunction with the oncogenic stimulus (often unknown), with determination of efficacy upon conclusion of a clinical trial (whether cancer incidence was lower in experimental group). Application of conventional chemopreventive strategies to melanoma presents multiple obstacles including long latency for tumor development, difficulties in patient monitoring and compliance, and potential long-term toxicity of any agent. This R21 application proposes a novel paradigm for melanoma chemoprevention which bypasses these obstacles. We hypothesize that episodic drug administration, targeting oxidative damage pathways in anticipation of each oncogenic stimulus (UV radiation), will confer long-term benefit as inferred by protection of nevi against oxidative stress/damage following acute UV exposure. We have performed preclinical testing in melanocytes, a mouse model of UV- induced melanoma and in patients with nevi using the drug N-acetylcysteine (NAC), a potent bioavailable antioxidant with a demonstrated safety record of oral use in humans. Our preliminary studies suggest that targeting oxidative damage pathways with NAC coincident with and following single UV exposure can protect mice against UV-induced melanoma, and that orally administered NAC can safely and reliably be delivered to nevi in patients as indicated by analysis of oxidative biomarkers. In the proposed studies we will first define the timing of NAC administration with respect to UV exposure for optimal protection against UV-induced melanoma in the mouse, and then perform a clinical trial in patients with nevi to establish that UV-induced oxidative stress/damage in nevi can be significantly reduced by NAC. We envision that patients could take NAC prophylactically in anticipation (and/or following) acute sun exposure to reduce UV-induced oxidative stress/damage in their nevi and melanocytes - thereby reducing their long-term risk of developing melanoma. PUBLIC HEALTH RELEVANCE: In addition to the hundreds of thousands of individuals in the U.S. with prior history of melanoma, there are many more who have multiple or atypical moles who are also at increased risk for melanoma. Thus millions of people could potentially benefit from implementation of an efficacious melanoma chemoprevention program. The proposed studies may lead to the development of a chemopreventive agent for acute UV exposure, such as a 'sunburn pill', which could be used prophylactically as an adjunct to sunscreen. This project is particularly timely given the increasing incidence of melanoma, and lack of available effective therapies for patients with advanced disease.